Summary Current globally used rotavirus vaccines are less effective in low-income settings (Vaccine Efficacy (VE)=40- 60%) compared to high-income settings (98%). Previously-studied risk factors for rotavirus vaccine failure, that is developing rotavirus diarrhea after a full course of immunizations, include high maternal rotavirus antibodies during pregnancy and breastfeeding, concomitant oral polio vaccine administration, and the high burden of co- enteric pathogens. These factors alone do not fully explain the reduced VE in low-income settings. One unexplored mechanism is the potential role of genetically determined susceptibility to rotavirus in rotavirus vaccine failure. Current vaccines exert their effect when the attenuated P[8] vaccine virus surface protein binds to histo-blood group antigen (HBGA) receptors in the gut, mimicking natural rotavirus infection. Rotavirus vaccines may be ineffective among individuals with no HBGA receptors. Mutations in FUT2 and FUT3 genes, which regulate expression of HBGAs, lead to null HBGA phenotypes (non-secretor and Lewis-negative). Production of HBGAs, and thus HBGA receptors, is prevented in these individuals. Recently, null HBGA phenotypes have demonstrated complete resistance to rotavirus serotype P[8], the sole P-component of current rotavirus vaccines. In high-income settings, individuals with null HBGA phenotypes are at low risk of vaccine failure because P[8] is the prevalent circulating serotype and these individuals are innately protected to P[8]. However, in low-income settings, such as sub-Saharan Africa, there is a greater prevalence of both non- P[8] serotypes and null HBGA phenotypes, compared to high-income settings. In these regions, individuals with null HBGA phenotypes may be at increased risk of rotavirus vaccine failure. The proposed study will be nested within the ongoing Vaccine Impact on Diarrhea in Africa (VIDA) study. We will collect saliva specimens in a subset of VIDA enrolled participants to determine Secretor and Lewis phenotypes. Existing comprehensive VIDA diarrheal surveillance, study infrastructure, and laboratory capabilities will be utilized. Building on our established collaboration, we will conduct a case-control study among children with a full course of rotavirus vaccinations in order to test whether Secretor or Lewis phenotype is associated with an increased risk of rotavirus diarrhea and serotype-specific rotavirus diarrhea. This will be the first study to examine host genetic risk factors as a mechanism for rotavirus vaccine failure. If we find that HBGA null phenotypes increase rotavirus vaccine failure we can answer vital remaining scientific questions related to low VE in sub-Saharan Africa. Additionally, accounting for innate susceptibility to rotavirus would be necessary in the development of future global rotavirus vaccines. If HBGA null phenotypes do not influence rotavirus vaccine failure, we can focus future research efforts on other risk factors which may contribute to rotavirus vaccine failure.